Review of patient‐reported outcomes (PROs) and non‐PROs in randomized controlled trials addressing head/neck cancers

Abstract Background To assess the frequency of patient‐reported outcomes (PROs) and non‐PROs in randomized controlled trials (RCTs) addressing head/neck cancers. Methods We included RCTs about interventions to treat head/neck cancers. PubMed was searched on September 16, 2022 and included studies published during three periods (2000–2002, 2010–2012, and 2020–2022). Data on types of outcomes and instruments to measure them were extracted and organized into PROs and non‐PROs, and temporal trends for reporting outcomes were determined. Results There was a reduction in the frequency of non‐PROs (40% to 22%) and an increase in PROs (5% to 19%) over 20 years. The frequency of reporting both non‐PROs and PROs seemed to be stable over the same period (55% to 58%). A great variety of instruments to measure PROs and non‐PROs was identified. Conclusions There has been a growth in the types of PROs in more recent years, and they were more frequently reported in RCTs. However, head/neck cancer trials with a combination of PROs and non‐PROs were the most prevalent.


| INTRODUCTION
Patient-reported outcomes (PROs) are pivotal in clinical research to understand whether therapies have in fact impacted the lives of patients.In contrast, relying only on outcomes from the perspective of the researcher provides a limited view of the potential impact of therapies.For example, Parmar et al. 1 is a systematic review of compiled evidence on the effect of chemotherapy for treating oral and oropharyngeal cancer.However, it only reports endpoints for survival and locoregional control.Similarly, researchers treating tongue carcinoma with a combination of surgical, radio, and chemical therapies have only reported data on survival and cancer recurrence. 2 One example of PRO is pain or discomfort after an intervention was applied. 3Ideally, clinical studies should present a mixture of PROs and non-PROs to provide a more comprehensive view of the effects of proposed therapies.
In the head and neck areas, the use of PROs is even more critical in oncology due to the devastating potential side effects of conventional therapies, such as chemotherapy and radiotherapy, which may be long-lasting or even permanent. 4To the best of our knowledge, a comprehensive overview of the types of outcomes in randomized controlled trials (RCTs) of interventions for treating head and neck cancers has not yet been published.
The objective of the present study was to provide a comprehensive mapping of non-PROs and PROs in RCTs involving the treatment of head and neck neoplasms.We also evaluated whether there was a temporal trend in reporting different types of outcomes.

| Research question
The following research questions were used to guide the conduct of the present study: (1) What kinds of non-PROs and PROs are reported in RCTs involving the treatment of head and neck neoplasms?(2) Are there any temporal trends in the reporting of PROs in RCTs involving the treatment of head and neck neoplasms?

| Eligibility criteria
Clinical studies in the form of RCTs of interventions to treat head and neck cancers were included.Furthermore, studies focusing on dealing with or avoiding the side effects of cancer treatments and supportive treatments for cancer were also included.When additional follow-ups of the original RCTs were found, we selected the article with the longest follow-up.Other types of study design and RCTs with other aims were excluded.Study protocols, secondary analyses of RCTs, Mendelian randomization designs, studies focusing on other types/areas of cancer, and studies with animals were also excluded.Articles in languages other than English were excluded.Articles reporting information on the same study were excluded.

| Definition of non-PROs and PROs
Non-patient-reported outcomes were defined as endpoints that could be measured from the perspective of the researcher; therefore, there was no involvement of patient feedback.In our study all outcomes that were measured from the perspective of the researcher were considered non-PROs.
Patient-reported outcomes were defined in our study as information reported by patients, with or without the use of a validated instrument, 5 that reflected the effects of the received therapies.
We included non-PROs in order to have a control group to be compared.In this way, the reader will better interpret the prevalence of PROs in comparison to non-PROs.

| Data search and selection
A sample of RCTs was searched in the PubMed database using a predefined strategy (as reported in File S1).The search strategy included medical subject headings (MeSH) terms connected by the Boolean operators "OR" and "AND."The search was conducted on September 16, 2022 and included articles published during three different periods: 2000-2002, 2010-2012, and 2020-2022.
The title and abstract of each article were first screened to determine inclusion, and if it appeared that an article did not meet the inclusion criteria, it was excluded, and the reason for exclusion was recorded.The full text of each article included from the title/abstract review (the first phase) was then scrutinized, and if the article did not meet the inclusion criteria based on this more in-depth review, it was excluded, and the reason for exclusion was recorded.Two reviewers (MG and CMF) independently selected a sample of 10% of eligible studies and achieved good agreement (at least 80%), with the remainder selected by one reviewer (MG), as recommended by a validated instrument to assess the methodological quality of systematic reviews. 6

| Data extraction
A spreadsheet (Excel) form was created and used to record the data extracted from outcomes reported in the RCTs.During the development of the extraction form, the two authors met for several sessions to refine the form so that the information could be extracted in the most accurate way possible.Data on the types of outcome measures were extracted and organized into PROs and non-PROs.We also extracted information on the instruments and approaches used to assess PROs and non-PROs.To produce the most accurate data extraction process, we transcript what RCT authors reported regarding the name of the instrument, or the form of measurement in a textual form.Furthermore, the following characteristics of the RCTs were extracted: (1) year of publication; (2)   20) primary outcome reported.As with the selection phase, two reviewers (MG and CMF) independently extracted data from a sample of articles, and the results were compared.If there was good agreement (at least 80%), then one reviewer (MG) extracted the remaining data.

| Data analysis
Categorical data were reported as frequencies and percentages.When applicable, medians and respective interquartile ranges (IQR) were reported.

| Included articles
The initial search retrieved 347 documents from the three predefined periods.After the initial review of the titles and abstracts, 131 articles were excluded.After the full text assessment, an additional 12 articles were excluded.The search and selection processes are illustrated in Figure 1.The search strategy is reported in File S1.A full list of included and excluded articles (with reasons for exclusion) is also reported in File S1.

| Characteristics of the studies
The majority of RCTs were published in oncology journals (n = 119, 58.33%).The most common RCT design was parallel (n = 203, 99.51%), and all of the studies had an interventional aim (n = 204, 100%).Most of the RCTs had two treatment arms (n = 187, 91.67%), and most of their protocols were registered (n = 128, 62.75%), predominantly in Clini calTr ials.gov (n = 72, 56.25%).The median IF of the journals was 4.856 (IQR = 4.936).Most of the RCTs used a combination of PROs and non-PROs (n = 122, 59.80%) and reported a primary outcome (n = 150, 73.53%).All information about the RCT characteristics is reported in Table 1.
Almost all the RCTs published in 2020-2022 had an ethics committee reported (n = 136, 97.84%) (Table S1).A majority of the RCTs published in 2010-2012 did not have a protocol registered (n = 30, 66.67%), but a larger majority had an ethics committee reported (n = 34, 75.56%) (Table S2).None of the RCTs published in 2000-2002 had a protocol registered (n = 20, 100%) (Table S3).Moreover, just under half of the RCTs published in 2000-2002 had an ethics committee reported (n = 9, 45%).All information about the RCT characteristics for the different periods is reported in Tables S1-S3.

| Types of instruments for assessing non-PROs and PROs
For the most frequent non-PRO (overall survival), the Kaplan-Meier Method was usually applied (Table 4).For the most frequent PRO (pain), the Visual Analog Scale (VAS), the Numerical Rating Scale (NRS), and the McGill Pain Questionnaire were used (Table 5).The Common Terminology Criteria for Adverse Events (CTCAE) was applied to assess the non-PRO "adverse events."Across the different periods, there was a growth of different versions of CTCAE.The detailed information on types of instruments used to assess non-PROs and PROs are reported in Tables S10-S15.

| Temporal trends
There has been an increase in the reporting of PROs over the last two decades, and a decrease of non-PROs during the same period.The frequency of RCTs reporting a combination of PROs and non-PROs was stable over the years.Figure 2 and Table S16 (in File S1) show the temporal trends in the reporting of the outcomes in the 204 RCTs.

| Key findings
This study assessed the types of outcomes used in RCTs on oncologic interventions in the head and neck areas.We found a great variety of outcomes and instruments to measure them in RCTs addressing interventions for the treatment of cancer in the head and neck area.We also found a substantial increase in different types of both non-PROs and PROs in more recent oncologic trials.PROs seemed to be reported more in recent years, although a great proportion of trials reported a combination of PROs and non-PROs in all the three time periods of the analysis.

| Interpretation of the findings
The great variety of types of outcomes in the head and neck interventions for cancer treatment may indicate that the research community intended to cover all aspects of research and understand the impact of these interventions and the corresponding research on patients´ health.In recent years, more attention has been paid to trying to understand how the different therapeutic approaches affect the individual life of a patient with cancer.Probably everyone will agree that the most important outcome is the survival of a patient with cancer.However, other important outcomes, such as quality of life, also play an important role for patients suffering from cancer and the clinicians working with them. 7ttention to the effects of cancer therapies is incredibly important in the head and neck area.Conventional therapies, such as chemotherapy and radiotherapy, can cause strong side effects that are temporary or permanent.

Characteristics
Frequency %

Year
For example, chemotherapy that may be used to treat lymphoma in the Waldeyer's ring 8 might impose temporary limitations on the patient due to mucositis, which makes deglutition very difficult.Radiotherapy in this area can also have a similar effect.However, depending on the level of radiation that is applied to the head and neck area, the effects can be more intense and long-lasting.Trismus 9 and osteoradionecrosis 10 are conditions that can be severe and strongly affect a patient's quality of life.
The great variety of PROs might be related to the large number of instruments used to assess PROs.For example, a recent systematic review 11 identified 116 different instruments to assess health-related quality-of-life outcomes after interventions for treating head and neck cancer.We also found a great variety of instruments used to measure non-PROs and PROs in the present sample of RCTs.Many of these instruments are validated or in process of validation.However, a great number of types of outcomes and instruments to measure them also make comparison among RCTs more difficult, for example, in the case of a meta-analysis is conducted.It would be important to determine the priorities for applying PROs and non-PROs in head and neck cancer research.By classifying the most important outcomes, it is possible to increase efficiency in research with the possibility of reproducibility of findings 12  team using similar methodology.For example, some trials have reported the effect of therapies on the saliva of patients with cancer in the form of "amount of saliva," "consistence of saliva," and "flow of saliva."Although this kind of approach can provide an overall comprehensive view of the effects of therapies, it might hinder the reproducibility of findings when new trials are planned for the same research question.Hence, determining the most important outcomes might help to increase efficiency in research and reduce waste with regard to resources. 13n interesting finding in our study is the attention given to the research questions in RCTs from different periods.We noticed an increase in RCTs dealing with side effects and the supportive treatment of patients with head and neck cancers during the last 20 years (p = 0.025, chi-squared test with Yates correction) (Tables S1-S3; File S1).This finding may mean that researchers are becoming more interested in the management of potential side effects that would limit the quality of life of patients with cancer.More recent trials also reported a greater number of protocol registrations in public registries, as well as ethics committee permissions to conduct the trials.One can argue that these findings can be explained by a greater awareness in society of the importance of robust methodological principles and ethical aspects regarding the treatment of patients with head and neck cancer.
It is important to reduce the gap between the assessment of PROs in oncological clinical research and the assessment of PROs in clinical practice.Some evidence suggests that only a few health practitioners in clinical oncology use PROs in routine cancer care. 14In other words, caregivers dealing with patients with cancer do not effectively listen to their patients.In the current study, the same outcome could be considered both non-PRO and PRO.The difference would be related to the perspective of who would provide feedback about the effect of the treatment, researcher, or patient.For example, xerostomia could be assessed by a standardized method to assess the degree of dry mouth (researcher's perspective) as well as a more subjective view on the impression of the patients about the dryness of their mouth.Probably, the most important outcome in this situation would be PRO because it might better reflect the effect of the therapy than that measured by the researcher.Therefore, it is pivotal that caregivers pay attention to what patients report about the effects of the applied therapies.

| Limitations and strengths
The present study has limitations.There was a difference in the number of trials included in each period examined, which makes a comparison challenging.However, this output was directly related to the predefined eligibility criteria, and the differences can be explained by T A B L E 5 Types of instruments utilized for patient-reported outcomes (PROs) of all 204 articles.

Outcome Measured by
an increase in the published number of RCTs in more recent years.This study also has strengths.To the best of our knowledge, this is the first study to assess PROs and non-PROs reported in RCTs related to the therapy of head and neck cancers.We also included a sizable number of RCTs that might be representative of the current approaches used by researchers to understand the effect of therapies on patients with head and neck cancers.

| CONCLUSIONS
This study reviewed important information on non-PROs and PROs within the study of the head and neck.It showed that there has been an increase in the reporting of PROs in more recent RCTs addressing head and neck cancers.The present findings provide an overall view of the types of outcomes in head and neck oncology and can support further discussion on the importance of these outcomes in planning future RCTs in the field.

F I G U R E 1
Flowchart of the selection process.T A B L E 1 Characteristics of the 204 included articles.
by another research The 20 most prevalent non-patient-reported outcomes (non-PROs) in the 204 included articles.The 20 most prevalent patient-reported outcomes (PROs) in the 204 included articles.
Types of instruments utilized for non-patient-reported outcomes (non-PROs) of all 204 articles.